Lung cancer is the leading cause of cancer death in the U.S., resulting in more than 157,000 deaths in 2010. Ninety percent of this horrific toll is caused by cigarette smoking, yet only 11-24% of smokers will die from lung cancer. It is imperative that we find ways to identify, at a relatively young age, those smokers who are susceptible to lung cancer, so they can be targeted for intensive preventive interventions. We hypothesize that smokers who extensively metabolically activate lung carcinogens in cigarette smoke will be at highest risk for lung cancer. We have developed a unique and innovative phenotyping method to potentially identify these smokers. This method focuses on two types of carcinogens believed to play a significant role in lung cancer development in smokers: polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines, typified by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We use deuterated phenanthrene [D10]Phe, a non- carcinogenic PAH with structural features and enzymology profile similar to that of carcinogenic PAH, as a probe substrate. We administer this compound, with FDA approval, to smokers and quantify the excretion of its product of metabolic activation [D10]phenanthrene tetraol [D10]PheT, in urine. We have shown that this phenotyping approach is practical, accurate and precise. There is a 20-fold variation among smokers in conversion of [D10]Phe to [D10]PheT and we hypothesize that the smokers who carry out this conversion most extensively are at highest risk for lung cancer. In this proposal, we will extend our ongoing studies with the following specific aims: 1. Carry out a study in smokers to determine whether there is overlap between those who extensively metabolize [D10]Phe to [D10]PheT, activate NNK by -hydroxylation, and inhale the greatest amount of tobacco smoke carcinogens as determined by nicotine metabolites. We hypothesize that there will be overlap among these extensive metabolism and exposure groups and that we can therefore identify these triple risk individuals. 2. Determine the pharmacokinetics of [D10]Phe in adolescents who have just started smoking and compare to our existing data on [D10]Phe metabolism in habitual smokers. 3. Determine the relationship between benzo[a]pyrene metabolism by the carcinogenic diol epoxide pathway and Phe metabolism in smokers. We hypothesize that the carcinogenic metabolism pathway of benzo[a]pyrene will correlate strongly with tetraol formation from Phe. 4. Further characterize the glutathione detoxification pathway of Phe by analysis of smokers' urine. The results of this proposal will vastly expand our understanding of lung carcinogen metabolism in smokers, thus providing new insights for tobacco control and lung cancer prevention. PUBLIC HEALTH RELEVANCE: Ninety percent of lung cancer, the leading cause of cancer death in the United States, is caused by cigarette smoking but only 11-24% of smokers get lung cancer. In this project, new methods are being developed which can potentially identify susceptible smokers at a young age. These smokers could be targeted for intensive smoking cessation measures to prevent lung cancer.